Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease

Xiaohan Li; Zekun Li; Hua Chen; Hongmin Guo; Yihao Ge; Fang Dong; Fan Zhang; Feng Zhang

doi:10.1016/j.intimp.2025.115199

Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease

Int Immunopharmacol. 2025 Jul 12:163:115199. doi: 10.1016/j.intimp.2025.115199. Online ahead of print.

Authors

Xiaohan Li¹, Zekun Li¹, Hua Chen², Hongmin Guo¹, Yihao Ge¹, Fang Dong³, Fan Zhang⁴, Feng Zhang⁵

Affiliations

¹ Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, PR China.
² Department of Orthopedic Rehabilitation Treatment, Hebei Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Cangzhou, China.
³ Department of Clinical Laboratory Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, PR China.
⁴ The Key Laboratory of Neural and Vascular Biology, Ministry of Education and Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050017, PR China. Electronic address: zhangfan86@hebmu.edu.cn.
⁵ Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, PR China. Electronic address: ydsyzf@hebmu.edu.cn.

PMID: 40652586
DOI: 10.1016/j.intimp.2025.115199

Abstract

Inflammation in both CNS and peripheral circulation system is known to have a significant impact in AD pathogenesis. In the CNS, AD-related inflammation involves the activation of various types of immune cells, such as microglia, astrocytes, and T cells. Meanwhile, one of the hallmarks of peripheral circulation inflammation in AD is activation of T cells. In addition, Apolipoprotein E4 (APOE4), as a key genetic risk factor for late-onset AD, significantly influences both CNS and peripheral circulation system inflammation in the pathogenesis of AD. Moreover, APOE4 play a key role in various pathological changes in AD, such as Aβ accumulation, tau phosphorylation, lipid metabolism disorders, and BBB dysfunction, resulting in microglia, astrocytes, and T cells activation, as well as the release of inflammatory factors. This comprehensive review aims to elucidate the specific mechanisms through which APOE4 triggers inflammation in both CNS and peripheral circulation system in the context of AD. Furthermore, we also summarize several therapeutic approaches that target APOE for the treatment of AD.

Keywords: Alzheimer's disease; Apolipoprotein E4; CNS inflammation; Peripheral circulation system inflammation.

Publication types

Review